Radioactive isotopes of many metallic elements have potential uses in the diagnosis and treatment of disease. The yttrium-90 isotope, for example, which has a half-life of 64 hours and emits a strong beta particle (Emax=2.28 MeV), has excellent promise in treating many human diseases, and recent advances in radioimmunotherapy and peptide targeted radiotherapy have created a great demand for 90Y. Another radioisotope, thallium-201, which has a half-life of 73 hours and emits photons of 135 and 167 keV, is widely used as a myocardial perfusion imaging agent. Numerous other examples of radioactive isotopes, and their potential use as radiopharmaceuticals are well known to those in the art.
One way to produce radioisotopes with potential use as radiopharmaceuticals is from the decay of radioactive species of elements from adjacent groups in the periodic table. For Example, 90Y can be produced from the 28-year half-life decay of 90Sr. Similarly, 201Tl is decayed from its parent 201Pb (T1/2=9.33 hour).
To be used as radiopharmaceuticals, the target isotopes generally need to be separated from the parent compounds. Many different techniques have been used to separate radioisotopes, including precipitation, solvent extraction, and ion-exchange chromatography, and the use of a number of organophosphorus extractants has been described. For example, di-2-ethylhexylphosphoric acid (DEHPA) has been widely used in extraction technology of rare earths and yttrium since the publication of Peppard, et al. (D. F. Peppard, et al., J. Inorg. Nucl. Chem. 4: 334, 1957) in 1957. DEHPA was also used in high level separations of fission products of rare earths and 90Y at Oak Ridge National Laboratory in 1959. A smaller scale procedure for millicurie quantities of 90Y was used at Oak Ridge National Laboratory (ORNL) (N. Case, et al., ORNL Radioisotope Manual, U.S.A.E.C. Report ORNL-3633, TID 4500, 30th edition, June 1964) from 1962 to 1990. This procedure was later modified for use in purification of reagents and is now used commercially to supply 90Y (J. A. Partridge, et al., J. Inorg. Nucl. Chem. 31: 2587–89, 1969; and Lane A. Bray, et al., U.S. Pat. No. 5,512,256, Apr. 30, 1996).
Another organophosphorus compound, 2-ethylhexyl 2-ethylhexylphosphonic acid (EHEHPA), was also developed by Peppard (D. F. Peppard, et al., J. Inorg. Nucl. Chem. 18: 245, 1961 and J. Inorg. Nucl. Chem. 27: 2065, 1965). This extractant became widely used to recover yttrium, other rare earths and trivalent actinides, because it was readily stripped with dilute acid. Several investigators have reported a specific preference for EHEHPA over DEHPA for yttrium recovery (Y. Mori, et al., Proc. Symp. Solvent Extr. 119–24, Jpn. Assoc. Solvent Extr. Hamamatsu, Japan, 1984; K. Inoue, et al., Nippon Kogyo Kaishi, 102: 491–4,1984; D. Li, et al., Int. Solvent Extr. Conf. (proc.) 3: 80–202, 1980; D. Li, et al., New Frontiers in Rare Earth Science and Applications, 1: 463–67, 1985; and P. V. Achuthan, et al., Separation Science and Technology, 35: 261–270, 2000).
The use of neutral organophosphorus compounds for recovery and purification of uranium, actinides and rare earths began in the 1950's (J. C. Warf, J. Am. Chem. Soc. 71: 3257, 1949) with tri-n-butyl phosphate (TBP). Other extractants with phosphine groups were tested in the 1960–70's with some success. The work at Argonne National Laboratory (R. C. Gatrone, et al., Solvent Extr. and Ion Exch. 5: 1075–1116, 1987) in developing a number of compounds of the carbamoylmethylphosphine oxides type led to a class of extractants for removing trivalent, quadri-valent and hexa-valent ions from nitric acid solutions. A number of papers from Argonne National Laboratory and from USSR in the 1980–83 period also demonstrated the use of the this type of extractant (D. G. Kalina, et al, Sep. Sci. Technol. 17: 859, 1981; T. Y. Medved, et al., Acad. Sci. U.S.S.R., Chem. Series, 1743, 1981; E. P. Horwitz, et. al., Sep. Sci. Technol. 17: 1261, 1982; M. K. Chmutova, et al., Sov. Radiochem. Eng. Transl. 24: 27, 1982; E. P. Horwitz, et al., Proceedings ISEC'83 1983; M. K. Chmutova, et al., J. Radioanal. Chem. 80: 63, 1983; A. C. Muscatello, et al., Proceedings ISEC'83, pp. 72, 1983; E. P. Horwitz, et al., Solvent Extr. Ion Exch. 3: 75, 1985; W. W. Shultz, et al., J. Less-Common Metals, 122: 125, 1986; J. N. Mathur, et al., Talanta, 39: 493–496, 1992; J. N. Mathur, et al., Waste Management, 13: 317–325, 1993). When using this technique, the ions are extracted as the metal nitrates from nitric acid solution. The extractants, loaded with the ions, are then back extracted with dilute acids or salt solutions (0.01–0.1N), which causes the ions to strip from the extractant, thereby permitting easy recovery without boil-down of the acids.
As noted above, 201Tl is produced by decay (electron capture) of its parent isotope, 201Pb. 201Pb is generally produced in a cyclotron by irradiating 203Tl with ˜30 MeV protons (203Tl(p, 3n)201Pb). Separation of 201Tl from the irradiated targets is traditionally performed in two steps. First, radioactive lead is separated from the 203Tl targets, and after an optimal waiting period to allow build up, the accumulated 201Tl daughter is separated from the parent lead isotopes. Various methods for performing the separation have been reported. E. Lebowitz, et al., J, Nucl. Med., 16:151–155 (1975), for example describes a production method in which EDTA complexing agent, hydrazine sulfate and a ion exchange column are first used to separate the lead activities from the thallium targets. Next, an anion exchange column is used to adhere the 201Tl+3 (oxidated by NaClO) and allow the lead activities to be eluted. Finally the 201Tl activity is then eluted with hot hydrazine-sulfate solution, reducing Tl+3 to Tl+1. S. M. Qaim, et al., Int J. Appl. Radiat. Isot., 30: 85–95, 1979, reported a procedure of precipitating quantitatively the carrier-free lead activities by Fe(OH)3 first, followed by an anion-exchange column separation of 201Tl. M. D. Kozlova, et al., Int J. Appl. Radiat. Isot., 35: 685–687, 1984, reported a procedure that includes the co-precipitation of the lead activities as strontium sulfate, followed by solvent extraction using butyl acetate and adding KBrO3 solution. J. L. Q. de Britto, et al., J. Radioanal. Nucl. Chem. Letters, 96: 181–186, 1985, reported a separation based on the properties of a chelating caboxylic acid ion exchange resin-column which at pH 4.5 retains lead while thallium is easily eluted. Both J. A. Campbell, et al., (J. Labelled Compounds and Radiopharmaceuticals, 13:437–443, 1977) and M. C. Lagunas-Solar, et al., (Int J. Appl. Radiat. Isot., 33: 1439–1443, 1982) suggested to use Dowex 50W-X8 system to adsorb lead and thallous ion, while thallic ion is eluted by 0.005N hydrochloric acid containing 0.1% chlorine gas. These methods all tend to be time consuming, hazardous, and expensive.
To be suitable for use in radiopharmaceuticals, it is also generally important for the radioisotope to be separated from the parent compounds to a high degree of purity. For example, for products containing 90Y, the level of 90Sr should be kept below 10−6Ci per Ci 90Y. Contamination by other metals such as Fe, Cu, Zn, and Ca should also be reduced, because the foreign metallic ions can compete with Y+3 for chelating agents that may be used in the pharmaceutical products. However, many different techniques for the separation of radioisotopes suffer from incomplete separation, and/or contamination by other metals. Consequently, the prior art has failed to provide a simple separation process for producing quality radioisotopes that meet these criteria.
Also, many of the known techniques have deficiencies in scaling up the separation process due to radiation damages to the materials and devices used in the separation. For example, J. S. Wike, et al., Appl. Radiat. Isot., 41: 861–865, 1990, discloses a separating technique using DEHPA in dodecane to extract 90Y. However, the complexity of the process, which involves repeated stripping of the organic extractant, leads to the accumulation of radiolysis products of the extractant in either the 90Sr stock solution or 90Y product. It is believed that both the DEHPA and radiolytic fragments of organic extractant cause the 90Y to stick to the wall of glass vessels used in the process, resulting in poor recovery of 90Y. Consequently, this method fails to provide a simple 90Sr/90Y separation process for producing quality 90Y in high yields.
Horwitz, et al., U.S. Pat. No. 5,368,736, discloses another separation technique that is capable of producing high decontamination factor of 90Y. This technique involves immobilizing strontium-selective extractant of hydrophobic crown ether carboxylic acid onto polymeric resin to selectively strip 90Sr away from 90Y after passing a 90Sr/90Y mixture through the crown ether column. The 90Y effluent is further purified by resin that is impregnated with rare-earth selective extractant, which is a mixture of octyl-(phenyl)-N,N-diisobutylcarbamoylmethylphosphine oxide (CMPO) and tri-butyl phosphate (TBP). The above separation technique avoids the use of organic solvent but requires at least three strontium-selective columns for the complete retention of 90Sr, which may limit its potential for multicurie scale-up. In addition this technique requires pH adjustment and volume concentration of 90Y between the crown ether and CMPO/TBP columns, which further complicate the process at the multicurie level.
Another present commercial method for supplying 90 y involves the extraction of 90Y from a mixture of 90Y and 90Sr using a DEHPA solvent extraction process that requires high concentrations of HNO3 or HCl (8–10 N) to strip the 90Y. When the excess acid is evaporated, the 90Y recombine with trace amounts (1–2 mg/liter) of DEHPA in the 90 y product, which results in loss of product on glassware (J. S. Wike, et al., J. Appl. Radiat. Isot., 41: 861–5, 1990), and in the shipping container. The recombination of 90Y with trace amounts of DEHPA can also result in precipitates, and incomplete tagging of the targeted molecule with 90Y. Consequently, the prior art has failed to provide a simple 90Sr/90Y separation process for producing quality 90Y in high yields.
What is needed is an improved method and apparatus for simple, low cost, separation of ions of metallic elements in aqueous solution, and, in particular, for separation of radioisotopes from their parent compounds. For example, a method that may be used to separate 90Y from 90Sr to provide 90Y ions with improved purity, concentrations and yields for use in radiotherapy. The process should also not require the use of any organic solvent, should minimize liquid waste discharge and also minimize waste of the radioactive parent